A modifier screen identifies DNAJB6 as a cardiomyopathy susceptibility gene

• DOI: 10.1172/jci.insight.88797
• Publication Date: 2016-09-07T15:01:49Z
• Authors: Yonghe Ding; Pamela A. Long; J. Martijn Bos; Yu-Huan Shih; Xiao Ma; Rhianna S. Sundsbak; Jianhua Chen; Yiwen Jiang; Liqun Zhao; Xinyang Hu; Jianan Wang; Yongyong Shi; Michael J. Ackerman; Xueying Lin; Stephen C. Ekker; Margaret M. Redfield; Timothy M. Olson; Xiaolei Xu
• Keywords: Genetic screen; Subfamily; Insertional mutagenesis

Mutagenesis screening is a powerful forward genetic approach that has been successfully applied in lower-model organisms to discover factors for biological processes. This phenotype-based yet be established vertebrates probing major human diseases, largely because of the complexity colony management. Herein, we report rapid strategy identifying modifiers cardiomyopathy (CM). Based on application doxorubicin stress zebrafish insertional cardiac (ZIC) mutants, identified 4 candidate CM-modifying genes, which 3 have linked previously CM. The long isoform DnaJ (Hsp40) homolog, subfamily B, member 6b (dnajb6b(L)) was as CM susceptibility gene, supported by identification rare variants its ortholog DNAJB6 from patients. Mechanistic studies indicated deleterious, loss-of-function modifying effects dnajb6b(L) can ameliorated inhibition ER stress. In contrast, overexpression dnajb6(L) exerts cardioprotective both fish and mouse models. Together, our findings establish mutagenesis scalable systematic CM, feasible suggest therapeutic targets, expandable other diseases.